RNA interference or “RNAi” is a term initially coined by Fire and co-workers to describe the observation that double-stranded RNA (dsRNA) can block gene expression when it is introduced into worms (Fire et al., Nature 391:806-811, 1998). Short dsRNA directs gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and has provided a new tool for studying gene function. This technology has been reviewed numerous times recently, see, for example Novina, C.D:, and Sharp, P., Nature 2004, 430:161, and Sandy, P., et al., Biotechniques 2005, 39:215, hereby incorporated by reference.
Influenza is one of the most widely spread infections worldwide. It can be deadly: an estimated 20 to 40 million people died during the 1918 influenza A virus pandemic. In the United States between 20 and 40 thousand people die from influenza A virus infection or its complications each year. During epidemics the number of influenza related hospitalizations may reach over 300,000 in a single winter season.
Several properties contribute to the epidemiological success of influenza virus. First, it is spread easily from person to person by aerosol (droplet infection). Second, small changes in influenza virus antigens are frequent (antigenic drift) so that the virus readily escapes protective immunity induced by a previous exposure to a different variant of the virus. Third, new strains of influenza virus can be easily generated by reassortment or mixing of genetic material between different strains (antigenic shift). In the case of influenza A virus, such mixing can occur between subtypes or strains that affect different species. The 1918 pandemic is thought to have been caused by a hybrid strain of virus derived from reassortment between a swine and a human influenza A virus. At present, there is a spreading concern about the potential emergence of novel influenza strains infective to humans, particularly from avian influenza variants, and more particularly from strain H5N1, by mixing in humans concurrently exposed to human and avian influenza virus. The close contact between agricultural birds and their human breeders familiar in most asian societies has experts convinced that it is not a question of whether but only when such a mixed strain will arise. A world-wide pandemic could swiftly ensue, with even graver consequences than in 1918.
Despite intensive efforts, there is still no effective therapy for influenza virus infection and existing vaccines are limited in value in part because of the properties of antigenic shift and drift described above. For these reasons, global surveillance of influenza A virus has been underway for many years, and the National Institutes of Health designates it as one of the top priority pathogens for biodefense. Although current vaccines based upon inactivated virus are able to prevent illness in approximately 70-80% of healthy individuals under age 65, this percentage is far lower in the elderly or immunocompromised. In addition, the expense and potential side effects associated with vaccine administration make this approach less than optimal. Although the antiviral drugs currently approved in the United States for treatment and/or prophylaxis of influenza are helpful, their use is limited due to concerns about side effects, compliance, and possible emergence of resistant strains.
US patent application 20040242518 and corresponding WO 04/028471, both filed Sep. 29, 2003, propose a limited number of RNAi agents for the treatment of influenza. Their efficacy in humans is not disclosed.
Therefore, there still remains a need for the development of effective therapies for the treatment and prevention of influenza infection in humans and animals, and particularly for therapies with high efficiency that allow the targeting of a broad range of influenza subtypes. One prerequisite for high efficiency is that the active ingredient is not degraded quickly in a physiological environment.